Cancer is an often fatal disease that affects a significant portion of the population. The National Cancer Institute estimated that the age-adjusted death rate due to cancer in the U.S. was 192.7 per 100,000 men and women per year. In January of 2003 approximately 10.5 million Americans had a history of cancer. Breast cancer is the most common malignancy in women, and is a major cause of mortality in women over 45 years of age, especially in United States. Each year over 185,000 new cases are diagnosed and more than 40,000 women die of the disease. However, only a very small percentage of breast and ovarian cancers is attributable to the inheritance of mutations in cancer susceptibility genes such as BRCA1 and BRCA2. The majority of breast and ovarian cancers require the knowledge of additional breast cancer genes for the diagnosis and treatment.
Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Cancer is caused by both external factors (tobacco, chemicals, radiation, and infectious organisms) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). The regulation of gene expression involved in cancer development has been heavily investigated, but therapeutics and methods for detecting cancer are still needed.
Germline mutations in the BRCA1 and BRCA2 genes account for increased susceptibility to familial breast and ovarian cancers (Nathanson, K. L., et al., Nat Med, 7:552-6 (2001)). BRCA1 encodes an 1863-amino acid protein with an N-terminal RING domain facilitating ubiquitination and a C-terminal BRCT domain stimulating transcriptional activation (Welcsh, P. L., et al., Trends Genet, 16:69-74 (2000)). The BRCT domain induces the cleavage of RNA polymerase II upon ionizing radiation (Bennett, C. B. et al., PLoS ONE, 3:e1448 (2008)). The sequence encoded by the large exon 11 of BRCA1 binds to Rad51, a protein critical for homologous recombination and DNA-damage response (Chen, J. J., et al., Cancer Res, 59:1752s-1756s (1999)). Alternative splicing variants of BRCA1, such as BRCA1Δ11b and BRCA1-IRIS (Wilson, C. A. et al., Oncogene, 14:1-16 (1997); ElShamy, W. M. & Livingston, D. M., Nat Cell Biol, 6:954-67 (2004)), have been identified with potential functional impact on BRCA1.
BRCA2 encodes a 3418-amino acid protein and has a very similar tissue expression pattern to BRCA1 (Chodosh, L. A., J Mammary Gland Biol Neoplasia, 3:389-402 (1998)). Its large exon 11 encodes eight sequence repeats called the BRC repeats, six of which interact with Rad51 (Bork, P., Blomberg, N. & Nilges, M., Nat Genet, 13:22-3 (1996); Bignell, G., et al., Hum Mol Genet, 6:53-8 (1997); Davies, A. A. et al., Mol Cell, 7:273-82 (2001)). Crystal structure analysis demonstrated that the BRC repeat mimics a motif between the interfaces of Rad51 oligomerization (Pellegrini, L. et al., Nature, 420:287-93 (2002)), and that the binding of BRCA2 to Rad51 is essential for both functions (Gudmundsdottir, K. & Ashworth, A., Oncogene, 25:5864-74 (2006)). The BRCA2 transcripts also undergo complex alternative splicing, and its splicing products are far from defined due to its large gene size (Speevak, M. D., et al., Eur J Hum Genet, 11:951-4 (2003); Bieche, I. & Lidereau, R., Cancer Res, 59:2546-50 (1999)).
The close functional relationship between BRCA1 and BRCA2 suggests the involvement in DNA-repair pathways in breast and ovarian cancers. However, the specific risk to breast and ovarian cancers that are evidently linked to hormone regulation has not been adequately explained. In addition, early linkage analysis at the chromosome 17q21 locus has provided substantial evidence for breast and ovarian cancer predisposition that is inherited in a Mendelian fashion in families with early onset cancers (Hall, J. M. et al., Science, 250:1684-9 (1990); Hall, J. M., et al., Am J Hum Genet, 50:1235-42 (1992); Narod, S. A., et al., Lancet, 338:82-3 (1991)). However, the BRCA1 mutations explained only a proportion of families with 17q21 association (Nathanson, K. L., et al., Nat Med, 7:552-6 (2001); Miki, Y., et al., Science, 266, 66-71 (1994)). This paradoxical phenomenon led to the speculation of the presence of an additional candidate gene within the BRCA1 locus (Vogelstein, B. & Kinzler, K. W., Cell, 79:1-3 (1994)). In 1995, during refined locus mapping near BRCA1 at 17q21, GT198 (genomic transcript 198, gene symbol PSMC3IP, also known as TBPIP or Hop2) was identified as a cDNA clone (Rommens, J. M., et al., Genomics, 28:530-42 (1995)). GT198 was later characterized as a nuclear receptor coregulator that interacts with nuclear receptors and is involved in estrogen, androgen and progesterone receptor-mediated gene regulation (Ko, L., et al., Mol Cell Biol, 22, 357-69 (2002); Satoh, T., et al., Endocrinology, 150:3283-90 (2009)). GT198 was also found to be homologous to yeast Hop2 (Petukhova, G. V., et al., Dev Cell, 5:927-36 (2003)), to interact with Rad51 and to stimulate DNA strand exchange in homologous recombination (Enomoto, R., et al., J Biol Chem, 281:5575-81 (2006); Pezza, R. J., et al., Genes Dev, 21:1758-66 (2007); Enomoto, R., et al., J Biol Chem, 279:35263-72 (2004)).
Existing BRCA1 and BRCA2 genes for detecting breast and ovarian cancer and treating cancer are typically insufficient, especially for a large amount of sporadic cancers.
Thus, it is an object of the invention to provide methods and compositions for the early detection or diagnosis of cancer, for example breast and ovarian cancer.
It is another object of the invention to provide compositions and methods for the treatment of one or more symptoms associated with cancer.
It is still another object to provide methods for screening for chemical compounds and small biological molecules such as antibodies that inhibit or alleviate pathologies due to cells having one or mutations resulting in cancer.
It is another embodiment to provide biomarkers for the detection and diagnosis of cancer.